WBR0106

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Endocrine
Prompt	[[Prompt::A 5-year-old girl is brought to the pediatrician's office by her mother. The child complains of the gradual onset of difficulty swallowing and hoarseness. She has a history of inability to produce tears and gastrointestinal distress that did not resolve with dietary modifications. She reports that her gastrointestinal symptoms have worsened and she now has recurrent bouts of diarrhea with little relation to food intake. Upon further questioning, the patient reports she is also experiencing occasional flushing episodes as well. Her blood pressure is 110/70 mmHg, heart rate is 66/min, and temperature is 36.8 °C (98.24 °F). On physical examination, the patient appears tall and slender. The physician also notes diffusely hypertrophied lips that contain numerous yellowish-white, sessile, painless nodules. The patient's eyelids are also thickened and everted. Laboratory studies are remarkable for elevated concentration of serum calcitonin. Development of which of the following tumors is this patient most at risk for?]]
Answer A	AnswerA::Pituitary adenoma
Answer A Explanation	[[AnswerAExp::Pituitary adenoma is associated with MEN 1 syndrome.]]
Answer B	AnswerB::Pheochromocytoma
Answer B Explanation	[[AnswerBExp::Pheochromocytoma is associated with MEN 2B syndrome.]]
Answer C	AnswerC::Insulinoma
Answer C Explanation	[[AnswerCExp::Insulinoma is associated with MEN 2A syndrome.]]
Answer D	AnswerD::Parathyroid adenoma
Answer D Explanation	AnswerDExp::Parathyroid tumors are associated with MEN 2A syndrome.
Answer E	AnswerE::Zollinger-Ellison syndrome
Answer E Explanation	[[AnswerEExp::Zollinger-Ellison syndrome is a gastrin-secreting tumor. It is associated with MEN 1 syndrome.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Multiple Endocrine Neoplasia type 2B (MEN 2B) is an autosomal dominant genetic disease due to a missense mutation of the RET (REarranged during Transfection) proto-oncogene that encodes a tyrosine kinase receptor. The syndrome features a marfanoid habitus, hyperflexible joints, and multiple neuromas on the buccal mucosa and eyes, with diffuse ganglioneuromatosis in the GI tract that manifest as constipation, diarrhea, or even megacolon at young age. Unlike other MEN syndromes, manifestations of MEN 2B typically start at early childhood, with mucosal neuromas usually being the presenting feature. Neuromas of the buccal mucosa lead to diffuse lip hypertrophy and the formation of painless palpable yellowish-nodules. The eyelids may be everted, and patients may be unable to produce tears due to the presence of neuromas within the ocular structures. Inability to tear may also be an early sign of MEN 2B and should raise the suspicion of the diagnosis before patients develop life-threatening cancers. The diagnosis is often suspected based on clinical features among patients with a positive family history of MEN 2B, or diseases that are frequently associated withe disease. Confirmation of the diagnosis should be made by genetic testing. Unlike cases of sporadic cancerous development, the hallmark of MEN-associated tumors is the presence of a precancerous hyperplastic state. MEN 2B mutation leads to bilateral C-cell hyperplasia (CCH), which eventually progresses to invasive medullary thyroid cancer (MTC) in almost 100% of cases, sometimes starting at childhood. Pheochromocytoma is another MEN-associated tumor; it occurs in 50% of cases. The patient has developed metastatic medullary carcinoma of the thyroid, a tumor of the parafollicluar C cells which produce calcitonin. While the patient previously had gastrointestinal symptoms due to MEN 2B, the new-onset dysphagia and hoarseness suggest the development of a neck tumor; whereas diarrhea, flushing, bone pain, and weight loss are all signs of metastatic medullary thyroid carcinoma. Educational Objective: MEN 2B syndrome is an autosomal dominant genetic disorder due to a missense mutation of RET proto-oncogene. Clinical features include a marfanoid habitus and mucosal neuromas. MEN 2 B syndrome is associated with early-onset medullary thyroid carcinoma and pheochromocytoma. References: Brauckhoff M, Machens A, Hess S, et al. Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: an exploratory analysis. Surgery 2008;144:1044-51 Fink A, Lapidot M, Spierer A. Ocular manifestations in multiple endocrine neoplasia type 2B. Am J Ophthalmol. 1998;126(2):305-7 Kebebew E, Clark OH. Medullary thyroid cancer. Curr Treat Options Oncol. 2000;1(4):359-67 Lee R, Hyer J, Chowdhury H, et al. Ocular signs of multiple endocrine neoplasia type 2B (MEN2B). J Clin Endocrinol Metab. 2012;97(3):725-6 First Aid 2014 page 329]]
Approved	Approved::Yes
Keyword	WBRKeyword::Multiple endocrine neoplasia, WBRKeyword::MEN, WBRKeyword::Endocrine, WBRKeyword::Cancer, WBRKeyword::Genetics
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